POS1427 GENETICALLY PROXIED THERAPEUTIC INHIBITION OF ANTIHYPERTENSIVE DRUG TARGETS AND RISK OF SYSTEMIC LUPUS ERYTHEMATOSUS: A MENDELIAN RANDOMIZATION ANALYSIS
Authors: S. Song, C. Wang, R. Zhao, J. Qiao, S. X. Zhang, X. LI
Journal: Annals of the Rheumatic Diseases (2023)

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by production of autoantibodies directed against nuclear and cytoplasmic antigens, affecting several organs. SLE is associated with a high burden of cardiovascular disease. Hypertension is frequent among patients with SLE and studies show that SLE patients are at a higher risk of experiencing hypertension events than the general population [1] . Alpha-adrenoceptor blockers, Angiotensin converting enzyme inhibitors (ACEI), Beta-adrenoceptor blockers (BB) and/or Calcium channel blockers (CCB) are generally recommended as the first-line antihypertensive therapy. Evidence from large randomized controlled trials comprehensively comparing risk of SLE of different classes of antihypertensive drugs is lacking. Objectives We used Mendelian randomization to investigate the potential effects of different antihypertensive drug classes on SLE. Methods We identified SNPs to proxy the protein targets of antihypertensive drugs on the basis that they mimicked the action of that drug on the target. Systolic blood pressure data were retrieved from the International Consortium of Blood Pressure Genome-Wide Association Studies, based on 757,601 individuals of European ancestry [2] . For each drug target, single-nucleotide polymorphisms (SNPs) in the drug target gene region (± 100kB) that were associated with SBP (p &lt; 5 × 10−8) were selected as proxies for drug target perturbation after clumping to a pairwise linkage disequilibrium threshold of r2 &lt; 0.3 using the 1000 Genomes European reference panel. Summary level statistics of SLE were obtained from the latest and most extensive GWAS database, including 14,267 individuals of European ancestry (5,201 cases and 9,066 controls) [3] . Mendelian randomization was then performed using the inverse variance weighted (IVW), MR-Egger and Weight Median (WM). If there was only a single variant available, we used the Wald ratio to estimate the effect. Results We found that a 1-SD decrease in blood ADRA1A expression (target for Alpha-adrenoceptor blocker) was associated with a lower risk of schizophrenia (IVW method, OR, 0.886, 95% CI, 0.841-0.934, P = 6.845×10−6). Genetically predicted effects of CACNB2 (target for CCB) decreased SLE risk (MR-Egger method, OR, 0.774, 95% CI, 0.660-0.908, P = 0.004; WM method, OR 0.929, 95% CI, 0.873-0.988, P = 0.019) (Figure 1). And other classes of antihypertensives drug targets had no effect on SLE risk. Conclusion Mendelian randomization suggests that CCB and Alpha-adrenoceptor blocker is likely to increase the risk of SLE. These findings warrant greater pharmacovigilance and further investigation into the effect of CCB and Alpha-adrenoceptor blockers on SLE susceptible population, as well as SLE patients with cardiovascular complications. References [1]Munguia-Realpozo P, Mendoza-Pinto C, Sierra Benito C, et al. Systemic lupus erythematosus and hypertension. Autoimmun Rev. 2019;18(10):102371. doi:10.1016/j.autrev.2019.102371. [2]Evangelou E, Warren HR, Mosen-Ansorena D, et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits [published correction appears in Nat Genet. 2018 Dec;50(12):1755]. Nat Genet. 2018;50(10):1412-1425. doi:10.1038/s41588-018-0205-x. [3]Bentham J, Morris DL, Graham DSC, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015;47(12):1457-1464. doi:10.1038/ng.3434.. Acknowledgements: NIL. Disclosure of Interests None Declared.